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Antipsychotics: Taking the Long View

By Thomas Insel, M.D., NIMH Director

One of the first lessons I received as a psychiatrist-in-training 35 years ago was the value of antipsychotic medications. These medicines have been available for the treatment of psychosis for over half a century, beginning with the prototype first generation drug chlorpromazine (Thorazine) and now extending to some 20 different compounds, including several second-generation medications, often called “atypical antipsychotics.” Symptoms such as hallucinations, delusions, and paranoia are reduced reliably by these drugs. Although these symptoms can be frightening and dangerous for patients, family members, and providers, antipsychotics safely and effectively help people through the crisis of acute psychosis.

However, the long-term management of chronic mental illness is another matter. Recently, results from several studies have suggested that these medications may be less effective for the outcomes that matter most to people with serious mental illness: a full return to well-being and a productive place in society.

That is not to say that people are not remitting or recovering from serious mental illness. An article recently posted online in JAMA-Psychiatry tells an interesting story about medications and recovery.1 Wunderink and colleagues from the Netherlands report on a seven-year follow-up of 103 people with schizophrenia and related disorders who had experienced a first episode of psychosis between 2001 and 2002. After six months of symptomatic remission following antipsychotic treatment, patients were randomly assigned to either maintenance antipsychotic treatment or a tapering-off and discontinuation of the drug. As expected, the group that stopped taking their medications experienced twice the relapse rates in the early phase of the follow-up. But these rates evened out after a few years, as some patients in the maintenance group also stopped taking their medication. Most important, by seven years, the discontinuation group had achieved twice the functional recovery rate: 40.4 percent vs. only 17.6 percent among the medication maintenance group. To be clear, this study started with patients in remission and only 17 of the 103 patients—21 percent of the discontinuation group and 11 percent of the maintenance group—were off medication entirely during the last two years of follow-up. An equal number were taking very low doses of medication—meaning that roughly one-third of all study patients were eventually taking little or no medication.

For me, there were three remarkable results in this study. First, the groups did not ultimately differ in their experience of symptoms: about two-thirds of each group reported significant improvement in symptoms at seven years. Second, 29 percent of the discontinuation group reported that they had also achieved a healthy outcome in work and family life—a number that should give hope to those struggling with serious mental illness. And finally, antipsychotic medication, which seemed so important in the early phase of psychosis, appeared to worsen prospects for recovery over the long-term. Or, as Patrick McGorry said in an accompanying editorial, “less is more.”2 At least for these patients, tapering off medication early seemed to be associated with better long-term outcomes.

What does this say about the long-term use of antipsychotics? Are they potentially harmful? Are they necessary for an individual’s entire lifetime? Earlier this year, Martin Harrow and Thomas Jobe reported an analysis of several long-term follow-up studies of people with schizophrenia to determine if antipsychotics, given long-term, facilitate a return to functional well-being.3 They describe the following pattern across these studies: (a) within the first 6-10 months after discontinuation, 25-55 percent of patients relapse; (b) for those who do not relapse during this period, subsequent relapses are much less frequent even after prolonged periods off medication.

It appears that what we currently call “schizophrenia” may comprise disorders with quite different trajectories. For some people, remaining on medication long-term might impede a full return to wellness. For others, discontinuing medication can be disastrous. For all, we need to realize that reducing the so-called “positive symptoms” (hallucinations and delusions) may be necessary, but is rarely sufficient for a return to normal functioning. Neither first nor second generation antipsychotic medications do much to help with the so-called negative symptoms (lack of feeling, lack of motivation) or the problems with attention and judgment that may be major barriers to leading a productive, healthy life. Family education, supported employment, and cognitive behavioral therapy have all demonstrated efficacy in reducing the likelihood of relapse events, increasing the ability to function in daily life, and improving problem-solving and interpersonal skills.

NIMH is supporting research on interventions that focus on a combination of approaches—symptom remission, family engagement, and functional recovery. The Recovery After Initial Schizophrenia Episode (RAISE) project combines low-dose medication with family psycho-education, supported education/employment, individual resilience training, and other interventions to focus on more than just the psychotic symptoms.4Combining current treatments, as done in RAISE, looks like a promising approach.5,6,7

We realize that for too many people, today’s treatments are not good enough. New, better treatments are essential if we are to improve outcomes for all – that is the promise of research. But in the meantime, we need to be thoughtful about the treatments we have. Clearly, some individuals need to be on medication continually to avoid relapse. At the same time, we need to ask whether in the long-term, some individuals with a history of psychosis may do better off medication. This is a tough call, where known risks need to be balanced against potential benefits. As the RAISE project has emphasized, shared decision-making between patients, families, and providers is essential for long-term management of psychotic disorders.

These new data on the long-term outcomes for people with “schizophrenia” remind us that 100 years after defining this disorder and 50 years after “breakthrough” medications, we still have much to learn.

This blog originally appeared on the NIMH Director's Blog. To read other blog entries from Dr. Thomas Insel, click here.

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